Thiazolidinediones, peroxisome proliferator-activated receptor γ agonists, regulate endothelial cell growth and secretion of vasoactive peptides

Fukunaga, Yasutomo; Itoh, Hiroshi; Doi, Kentaro; Tanaka, Takuma; Yamashita, Jun; Chun, Tae Hwa; Inoue, Mayumi; Masatsugu, Ken; Sawada, Naoki; Saito, Takatoshi; Hosoda, Kiminori; Kook, Hyun; Ueda, Makiko; Nakao, Kazuwa

doi:10.1016/s0021-9150(01)00430-0

Cited by 100 publications

(68 citation statements)

References 34 publications

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“…The thiazolidinediones inhibit vascular smooth muscle and endothelial cell migration and proliferation of both animal and human cell lines 66,67 and reduce atherosclerosis in the LDL-receptor-null mouse model. 68 Likewise, controlled clinical trials with treatment durations ranging from 6 to 18 months have reported favorable effects on carotid intimamedia thickness 69 -73 (Figure 2) and restenosis after percutaneous coronary intervention 74 -78 (Figure 3).…”

Section: Atherosclerosis Development and Progressionmentioning

confidence: 99%

New Drugs for the Treatment of Diabetes Mellitus

2008

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Section: Atherosclerosis Development and Progressionmentioning

confidence: 99%

New Drugs for the Treatment of Diabetes Mellitus

2008

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“…Chronic hypoxiainduced increases in Nox4 were also associated with reductions in the expression of the nuclear transcription factor, peroxisome proliferator-activated receptor g (PPARg), in HPASMCs and human pulmonary artery endothelial cells (HPAECs) (12). PPARg, an important regulator of lipid and glucose metabolism (14), modulates growth and proliferation of ECs (15) and SMCs (16). Activation of PPARg with the synthetic ligand rosiglitazone attenuates hypoxia-induced increases in mouse lung Nox4 expression in vivo (12) and in HPAECs (12) and HPASMCs (13) in vitro.…”

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confidence: 99%

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation

Green

Murphy

Kang

et al. 2012

Am J Respir Cell Mol Biol

134

147

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Increased NADP reduced (NADPH) oxidase 4 (Nox4) and reduced expression of the nuclear hormone receptor peroxisome proliferator-activated receptor g (PPARg) contribute to hypoxiainduced pulmonary hypertension (PH). To examine the role of Nox4 activity in pulmonary vascular cell proliferation and PH, the current study used a novel Nox4 inhibitor, GKT137831, in hypoxiaexposed human pulmonary artery endothelial or smooth muscle cells (HPAECs or HPASMCs) in vitro and in hypoxia-treated mice in vivo. HPAECs or HPASMCs were exposed to normoxia or hypoxia (1% O 2 ) for 72 hours with or without GKT137831. Cell proliferation and Nox4, PPARg, and transforming growth factor (TGF)b1 expression were measured. C57Bl/6 mice were exposed to normoxia or hypoxia (10% O 2 ) for 3 weeks with or without GKT137831 treatment during the final 10 days of exposure. Lung PPARg and TGF-b1 expression, right ventricular hypertrophy (RVH), right ventricular systolic pressure (RVSP), and pulmonary vascular remodeling were measured. GKT137831 attenuated hypoxia-induced H 2 O 2 release, proliferation, and TGF-b1 expression and blunted reductions in PPARg in HPAECs and HPASMCs in vitro. In vivo GKT137831 inhibited hypoxia-induced increases in TGF-b1 and reductions in PPARg expression and attenuated RVH and pulmonary artery wall thickness but not increases in RVSP or muscularization of small arterioles. This study shows that Nox4 plays a critical role in modulating proliferative responses of pulmonary vascular wall cells. Targeting Nox4 with GKT137831 provides a novel strategy to attenuate hypoxiainduced alterations in pulmonary vascular wall cells that contribute to vascular remodeling and RVH, key features involved in PH pathogenesis.Keywords: rosiglitazone; PPARg; TGF-b; pulmonary hypertension Pulmonary hypertension (PH) is a progressive disorder associated with significant morbidity and mortality. Although recent therapeutic advances have improved survival for patients with PH, the prognosis remains poor (1). The pathobiology of PH is complex, and factors that contribute to endothelial dysfunction have been implicated in pathogenesis (2, 3). Among these factors, NADP reduced (NADPH) oxidase enzymes that produce reactive oxygen species (ROS) contribute to the development of a variety of vascular diseases, such as atherosclerosis (4) and systemic (5) and pulmonary hypertension (6). NADPH oxidases catalyze the reduction of molecular oxygen to generate superoxide (O 2 .2 ), hydrogen peroxide (H 2 O 2 ), or secondary oxidants (7). Seven isoforms of the catalytic moiety of the nonphagocytic NADPH oxidase enzyme have been described (Nox1-5, Duox1-2). These subunits are homologous to the catalytic moiety of the prototype phagocytic NADPH oxidase Nox2 (or gp91 phox ) but differ from each other regarding cellular localization, tissue distribution, regulation, activation, and expression (7,8). For example, although both Nox1 and Nox4 are expressed in vascular smooth muscle cells (VSMCs), they are targeted to discreet intracellular locations, are differe...

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“…Indeed, patients with mutations in PPAR␥ imparting dominant negative activity on the receptor, exhibit early onset hypertension and insulin resistance. 9 Moreover, TZDs have been shown to attenuate the development of atherosclerotic lesions, 10 increase the release of vasodilators such as nitric oxide 11 and c-natriuretic peptide, 12 and decrease expression of angiotensin receptors 13 and endothelin. 14 These effects of TZDs have been predominantly elucidated either in cell culture, models of insulin-resistance, or models with only acute changes in blood pressure.…”

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PPARγ Agonist Rosiglitazone Improves Vascular Function and Lowers Blood Pressure in Hypertensive Transgenic Mice

et al. 2004

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Abstract-The peroxisome proliferator activated receptor (PPAR␥) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R ϩ A ϩ ). Rosiglitazone decreased systolic (138Ϯ5 versus 128Ϯ5 mm Hg) and mean blood pressure (145Ϯ5 versus 126Ϯ7 mm Hg) of R ϩ A ϩ mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R ϩ A ϩ mice when compared with littermate controls (RA Ϫ ). There were no effects of rosiglitazone on RA Ϫ mice; however, relaxation to acetylcholine (49Ϯ10 versus 82Ϯ9% at 100 mol/L) and nitric oxide (51Ϯ11 versus 72Ϯ6% at 10 mol/L) was significantly improved in treated R ϩ A ϩ mice. Rosiglitazone treatment of R ϩ A ϩ mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein.In separate studies, carotid arteries from R ϩ A ϩ and RA Ϫ mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPAR␥-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester (200 mol/L) or the PPAR␥ antagonist bisphenol A diglycidyl ether; 4,4Ј-isopropylidenediphenol diglycidyl ether (100 mol/L). These data suggest that in addition to potential genomic regulation caused by PPAR␥ activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function. Key Words: nitric oxide Ⅲ angiotensin Ⅲ endothelin Ⅲ carotid P eroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and bind to DNA as a heterodimer with retinoid x receptor to regulate transcription. Three genes encode different PPARs (␣, ␤/␦, and ␥), and the gene products are differentially expressed in a variety of tissues. 1 PPARs have been most widely characterized with respect to their role in adipocyte growth and differentiation. 2 More recently, PPAR␥ has become the focus of attention for the treatment of noninsulin-dependent diabetes mellitus, due largely to successful treatment with the thiazolidinedione (TZD) class of drugs that act as specific PPAR␥ ligands. TZDs (ie, troglitazone, ciglitazone, pioglitazone, and rosiglitazone) activate PPAR␥, leading to improved insulin sensitivity and reduced blood pressure in both humans and animals through a mechanism that has not been completely elucidated. [3][4][5][6] These findings, coupled with the observation that PPAR␥ is expressed in both vascular muscle 7 and endothelium, 8 suggest that it may play an important role in the regulati...

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Thiazolidinediones, peroxisome proliferator-activated receptor γ agonists, regulate endothelial cell growth and secretion of vasoactive peptides

Cited by 100 publications

References 34 publications

New Drugs for the Treatment of Diabetes Mellitus

New Drugs for the Treatment of Diabetes Mellitus

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation

PPARγ Agonist Rosiglitazone Improves Vascular Function and Lowers Blood Pressure in Hypertensive Transgenic Mice

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